tbuckley/cabot-search huggingface dataset:
Abstract 2819: Genome-wide CRISPR screen identifies NANP as a radio-sensitizing target of GBM by regulating NF-κB pathway
Authors: Yingwen Ding, Ze-Yan Zhang, Ravesanker Ezhilarasan, Aram S. Modrek, Jerome Karp, Erik P. Sulman
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) are the most malignant primary central nervous system tumors. The standard of care for newly diagnosed GBM patients includes surgery followed by combined radiation therapy (RT) and adjuvant temozolomide (TMZ) therapy. However, one of the therapeutic challenges is the inevitable resistance and recurrence after radiotherapy. Glioblastoma stem cells (GSC) are tumor initiating cells for GBM and plays key roles in radio resistance. Thus, we performed a genome-wide CRISPR screen using a radiation resistant GSC to identify potential RT sensitizing targets. We identified 139 potential RT sensitizing targets with a filter for only those genes associated with a greater than 2-fold reduction in representation with a p&amp;lt;0.05. There were 22 genes with a direct function in key DNA double-strand break repair pathways including 5 genes central to non-homologous end-joining (NHEJ1, XLF, PRKDC, DCLRE1C, XRCC4, LIG4), 6 genes involved in homologous recombination (RAD51D, CYREN, ATM, TONSL, BRCA2, RFWD3), and 7 genes central to initial DNA damage sensing (RNF8, RNF168, TP53BP1, RAD17, FOXM1, RAD9A, RAD1). These results are consistent with the crucial role of DNA repair following radiation exposure and demonstrate the success of the screening. Besides that, one of the top hits is NANP (N-acylneuraminate-9-phosphatase), which is involved in sialic acid synthetic pathway. Knocking down of NANP causes more G2/M arrest followed by apoptosis after radiation. γH2A.X staining and comet assay shows more DNA damage in NANP knock down cells after radiation. Transcriptome analysis reveals NANP inhibition restrain mesenchymal status and NF-κB pathway activation. Furthermore, activation of NF-κB pathway could rescue the RT-induced G2/M arrest of NANP knock down cells. TCGA and CGGA dataset shows NANP is highly expressed in GBM patients and patients with NANP high expression have poorer survival. In conclusion, our study identified NANP as a novel radio-sensitizing target for glioblastoma by regulating NF-κB pathway and mesenchymal status of GSCs. Citation Format: Yingwen Ding, Ze-Yan Zhang, Ravesanker Ezhilarasan, Aram S. Modrek, Jerome Karp, Erik P. Sulman. Genome-wide CRISPR screen identifies NANP as a radio-sensitizing target of GBM by regulating NF-κB pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2819.
Abstract 505: Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells
Authors: Priscilla Chan, Lian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, Steve A. Kay
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor, claiming the lives of roughly 10,000 Americans each year. Despite being the first cancer analyzed through the Cancer Genome Atlas, treatment success remains minimal, resulting average survival time of patients is 15 months following diagnosis and a five-year survival rate is 6.8%. One of the major challenges in treating GBM is the presence of GBM stem cells (GSCs) that are resistant to temozolomide (TMZ) chemotherapy and radiation, which is part of the current standard of care for GBM following maximal surgical resection. We found, however, that GSCs have a unique dependence on core circadian clock proteins, Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK), which is not observed in differentiated GBM cells or normal neuronal stem cells. Here we explore the use of novel small molecule circadian clock compounds that either lower BMAL1 transcription (REV-ERB agonists) or inhibit BMAL1::CLOCK heterodimer transcriptional activity (Cryptochrome (CRY) stabilizers or Casein Kinase (CK) 1/2 inhibitors) in targeting GSCs in in vitro patient derived cell lines and in in vivo GBM patient-derived xenograft (PDX) models. GSCs display increased sensitivity to clock compounds at single agent and combinations of clock compounds compared to non-cancerous cells, U2OS human osteosarcoma cells, and differentiated GSCs. Additionally, clock compounds are significantly more effective in targeting GSCs than TMZ. The clock compound SHP1705 increased over survival and delayed tumor growth in GBM PDX models. These results highlight the therapeutic potential small molecule circadian clock compounds have against GBM as both a single agent and adjuvant to existing therapies by specifically targeting the GSC population. Citation Format: Priscilla Chan, Lian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, Steve A. Kay. Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 505.
Abstract 2239: Investigation of the molecular biological significance of YAP/TAZ expression in PNEN
Authors: Yuta Shiraishi, Hiromitsu Hayashi, Daisuke Ogawa, Shinsei Yumoto, Hiroki Sato, Takashi Matsumoto, Toru Takematsu, Masataka Maruno, Masayo Tsukamoto, Tatsunori Miyata, Shigeki Nakagawa, Kosuke Mima, Hidetoshi Nitta, Hideo Baba
Journal: Cancer Research (2023)

Abstract [Background] Neuroendocrine neoplasms (NEN) developing in the digestive organs are relatively rare tumors, with 3 to 5 new cases per 100,000 population annually, most of which occur in the pancreas and digestive tract. In pancreatic neuroendocrine neoplasms (PNEN), the risk of metastasis and progression varies depending on the grade of the tumor, even when the tumor size is small. In clinical practice, it is often difficult to determine the indication for surgery or multidisciplinary treatment with chemotherapy. The mechanisms of tumor formation and progression in PNEN remain unknown. YAP/TAZ have been known to play an important role in pancreatic development. Here, we explore the biological and clinical significance of YAP/TAZ over-expression in PNEN. [Methods] Immunostaining for YAP/TAZ was performed using 92 resected specimens in PNEN patients, and the association between YAP/TAZ overexpression and clinicopathological factors was elucidated. Furthermore, we generated a PNEN cell line with YAP and TAZ over-expression using QGP-1, and examined the intracellular signals regulated by YAP/TAZ expression. [Results and Discussion] The overexpression of YAP, TAZ, and YAP/TAZ were observed in 55, 55, and 32patients, respectively. High YAP expression was significantly associated with positive lymphovascular invasion (p=0.04). YAP/TAZ-high group displayed significantly worse Overall survival (p=0.0023) and recurrence-free survival (p=0.007) compared to those in others. By Western-blotting, YAP/TAZ overexpression in the QGP-1 cell line enhanced phosphorylation of Akt and Erk1/2. [Conclusions] High expression of YAP/TAZ in PNEN was implicated in poor prognosis, and was also associated with Akt, Erk1/2, and mTOR. Citation Format: Yuta Shiraishi, Hiromitsu Hayashi, Daisuke Ogawa, Shinsei Yumoto, Hiroki Sato, Takashi Matsumoto, Toru Takematsu, Masataka Maruno, Masayo Tsukamoto, Tatsunori Miyata, Shigeki Nakagawa, Kosuke Mima, Hidetoshi Nitta, Hideo Baba. Investigation of the molecular biological significance of YAP/TAZ expression in PNEN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2239.
Abstract 3751: Characterizing the role of the y chromosome-expressed long non-coding RNA linc-SPRY3 family in lung cancer radiation resistance
Authors: Emily S. Westemeier-Rice
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. A major issue for clinicians and patients alike is inherent resistance to radiation therapy. Recently, certain long non-coding RNAs (lnc-RNAs) have been shown to regulate pathways involved in resistances to lung cancer treatments. Our group recently published that a group of long non-coding RNAs, named the linc-SPRY3 family, play an important role in radiation therapy sensitivity. Originating from the Y-Chromosome, these long non-coding RNAs have been shown in vitro and in vivo to decrease the tumor burden after radiation. Interestingly, certain male Non-Small Cell Lung Cancer (NSCLC) cell lines have been shown to have complete loss of the Y-chromosome (LOY), showing a radiation resistant phenotype. To test this, the DYZ1 region of the Y-chromosome, where the linc-SPRY3 family is expressed, was artificially introduced into radiation resistant male NSCLC cell lines with LOY. Remarkably, by adding the DYZ1 region of the Y-chromosome into these cells, they became more sensitive to radiation and had increased apoptosis. Based on this preliminary data, we hypothesize the linc-SPRY3 family interacts with important pathways in the cell to increase sensitivity to DNA double strand breaks. Through RNA-Sequencing and other preliminary experiments, we found that the linc-SPRY3 family regulates the expression of Cell Division Cycle 6 (CDC6) and Cell Division Cycle 25A (CDC25A) genes. Preliminary data suggests these interactions play a role in influencing NSCLC ability to invade and metastasize. We are currently characterizing this family of linc-RNAs by flow cytometry, in vivo metastasis models, and fluorescent in situ hybridization. We will characterize the mechanism of the linc-SPRY3 family in radiation resistance through genetic modifications and further downstream analysis via the over-expression and knockdown of these linc-RNAs. The characterization of these linc-RNAs will be critical for the development of potential diagnostic or therapeutic therapies. Citation Format: Emily S. Westemeier-Rice. Characterizing the role of the y chromosome-expressed long non-coding RNA linc-SPRY3 family in lung cancer radiation resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3751.
Abstract 1603: The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line
Authors: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol
Journal: Cancer Research (2023)

Abstract Osteoblastic bone metastasis is the predominant phenotype observed in advanced prostate cancer and is associated with high patient mortality and morbidity. WNT signaling is necessary for both bone formation and tumor progression. Dickkopf-1 (DKK-1), a secretory antagonist of the canonical WNT/β-catenin signaling pathway, plays a complex role in bone tumors since it can either promote or decrease tumor occurrence and metastasis. The present study explored the molecular role of DKK-1 in prostate tumor progression, metastasis, and tumor-bone interactions using the osteoblastic canine prostate cancer cell line, Probasco. Previously, we found that DKK-1 can inhibit bone mineralization of mouse calvaria by Probasco conditioned medium (CM). Now we stably expressed DKK-1 in Probasco cells (Probasco-DKK-1), which were injected into the tibias or left ventricle of athymic mice. Bone metastases were monitored by bioluminesent imaging, microCT, and histopathology. Our results showed that Probasco-DKK-1 bone metastases had increased tumor growth, increased osteoclastic bone resorption, and decreased intramedullary woven bone formation in vivo. In vitro, DKK-1 had an autocrine effect on Probasco cells, which altered the cell morphology, increased cell proliferation, and induced EMT. Mechanistically, DKK-1 had little effect on the canonical WNT/β-catenin signaling while dramatically down-regulated the non-canonical WNT/JNK signaling, which inhibited caspase-dependent apoptosis in Probasco-DKK-1 cells. To investigate the effect of Probasco-DKK-1 on bone cells, primary osteoblasts and osteoclasts were treated by CM collected from cancer cells. We found that DKK-1 did not inhibit the mineralization of osteoblasts nor stimulate the activity of osteoclasts directly, but the expression of RNAKL was significantly higher in Probasco-DKK-1 CM-treated osteoblasts. Therefore, the Probasco-DKK-1 cells enhanced the activity of osteoclasts indirectly via the regulation of osteoblasts, which induced bone resorption. In conclusion, we showed that DKK-1 promoted prostate tumor growth by stimulating cell proliferation and inhibiting apoptosis in a canonical WNT-independent manner and attenuated the osteoblastic activity of prostate cancer. These findings provide new insights into the molecular mechanisms of DKK-1 in tumor progression. Citation Format: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol. The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1603.
Abstract 3733: Disconnect between APOBEC3 expressions and mutations across cancers
Authors: Azad Khosh, Hamid Hamidi, Hamzeh Rahimi, Diako Ebrahimi
Journal: Cancer Research (2023)

Abstract DNA of many tumors is barraged by C-to-T/G mutations within TCW (W:T,A). These mutations are attributed to the aberrant expression and activity of APOBEC3 enzymes. They have been shown to account for many driver mutations in genes such as PIK3CA, ERBB2, and PPP2R1A, however their precise source and also their roles in tumor development, evolution, and patient survival are debated. Currently, quantification of APOBEC3 expression changes in tumor cells is confounded by the ubiquitous expression of these enzymes in infiltrating immune cells. In this study, we used quantitative biology approaches to separate the expression profiles of APOBEC3 enzymes in tumor and tumor microenvironment cells and determine their associations with tumor mutational signatures. For this purpose, we analyzed diverse datasets including TCGA tumor/matched normal RNAseqs, tumor somatic mutations, cell line RNAseqs and mutations, estimates of tumor purities and immune cell compositions, and expression of purified cell populations to precisely determine how APOBEC3 enzymes are dysregulated across tumors and whether their dysregulations are proportional to tumor mutational signatures. Unexpectedly, we found that dysregulation of APOBEC3 enzymes is independent of tumor C-to-T/G mutational burden. Importantly, our data suggest that this disconnect is likely not due to the episodic bursts of APOBEC3-induced mutations in cancer. Citation Format: Azad Khosh, Hamid Hamidi, Hamzeh Rahimi, Diako Ebrahimi. Disconnect between APOBEC3 expressions and mutations across cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3733.
Abstract 2036: Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
Authors: Michael Mumphrey, Noshad Hosseini, Abhijit Parolia, Jie Geng, Weiping Zou, Malini Raghavan, Arul Chinnaiyan, Marcin Cieslik
Journal: Cancer Research (2023)

Abstract Disruption of antigen presentation via loss of MHC expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. We developed the personalized genomics algorithm Hapster and accurately called somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1663 nonsynonymous mutations that provide key insights into MHC mutagenesis. We found that MHC-I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC-II mutations are more restricted. Recurrent deleterious mutations are found within haplotype and cancer-type specific hotspots associated with distinct mutational processes. Functional classification of MHC residues revealed significant positive selection for mutations disruptive to the B2M, peptide, and T-cell binding interfaces, as well as MHC chaperones. At the cohort level, all cancers with positive selection for MHC mutations are responsive to immune checkpoint inhibitors, underscoring the translational relevance of our findings. Citation Format: Michael Mumphrey, Noshad Hosseini, Abhijit Parolia, Jie Geng, Weiping Zou, Malini Raghavan, Arul Chinnaiyan, Marcin Cieslik. Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2036.
Abstract 3777: MicroRNA-inducible CRISPR/Cas9 for cell type-specific genome regulation in cancer
Authors: Seung Ja Oh, Cheol-Hee Shin, Ji Min Lee, Juyong Lee, Su Chan Park
Journal: Cancer Research (2023)

Abstract MicroRNA-dependent mRNA decay plays an important role in gene silencing by facilitating posttranscriptional and translational repression. Inspired by this intrinsic nature of microRNA-mediated mRNA cleavage, here, we describe a microRNA-targeting mRNA as a switch platform called mRNA bridge mimetics to regulate the translocation of proteins. We applied the mRNA bridge mimetics platform to Cas9 protein to confer it the ability to translocate into the nucleus via cleavage of the nuclear export signal called CRISPR Self Check-In. This system performed programmed gene editing in vitro and in vivo. Combinatorial treatment with cisplatin and miR-21-EZH2 axis-targeting CRISPR Self Check-In improved sensitivity to chemotherapeutic drugs in vivo. Using the endogenous microRNA mediated mRNA decay mechanism, our platform is able to remodel a cell’s natural biology to allow the entry of precise drugs into the nucleus, devoid of non-specific translocation. The mRNA bridge mimetics strategy is promising for applications in which the reaction must be controlled via intracellular stimuli and modulates Cas9 proteins to ensure safe genome modification in diseased conditions. Citation Format: Seung Ja Oh, Cheol-Hee Shin, Ji Min Lee, Juyong Lee, Su Chan Park. MicroRNA-inducible CRISPR/Cas9 for cell type-specific genome regulation in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3777.
Abstract 2797: Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years
Authors: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada
Journal: Cancer Research (2023)

Abstract Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged &amp;gt;75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75-87) years; male/female ratio, 70/29; performance status (PS) 0-1/2-3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I-III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS &amp;lt;1%/1%-49%/≥50%, 12/31/48; and monotherapy/combination therapy, 65/34. The best overall efficacy was CR/PR/SD/PD (7/40/32/20), and the response rate was 47.5%. The median progression-free survival (PFS) and overall survival (OS) were 8.0 and 19.0 months, respectively. The adverse event profile was generally similar to that reported in previous studies. In total, 77 blood samples were collected immediately before the second cycle (C1 trough). Although no clear association between Pemb concentrations and patient background was found, PFS and OS were significantly shortened in the population with low C1 trough, a population characterized by lower PS, high number of metastatic organs at the beginning of treatment, and low blood albumin level. Conclusion: In older adults aged &amp;gt;75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Citation Format: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada. Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2797.